Preparation and purification method of exomethylenetetrahydrophthalic anhydride and its application in the preparation of tandospirone

Abstract

The invention relates to a preparation method of exomethylenetetrahydrophthalic anhydride, a refining method thereof and an application thereof in a method for preparing tandospirone. The present invention combines the depolymerization of dicyclopentadiene, the cycloaddition of cyclopentadiene and maleic anhydride, and the transformation of endomethylene tetrahydrophthalic anhydride in series to complete the three-step reaction efficiently in one step, and the method does not need to carry out dicyclopentadiene separately. The depolymerization of dienes without separation of intermediate products generated by the reaction effectively solves the complicated depolymerization of dicyclopentadiene, low conversion rate and low yield in the existing preparation method of exomethylenetetrahydrophthalic anhydride , serious environmental pollution, high energy consumption, long production cycle, harsh storage conditions and other defects, and has the advantages of high yield, good quality, environmentally friendly use of solvents, low cost, and is suitable for industrialized large-scale production.

Description

technical field [0001] The invention belongs to the field of compound synthesis, and particularly relates to a preparation method of exo-methylenetetrahydrophthalic anhydride, a purification method thereof, and its application in the method for preparing tandospirenone or an analog thereof. Background technique [0002] Tandospirone is a third-generation anxiolytic after benzodiazepine (BDZ), which acts as serotonin 1A (5-HT 1A ) receptor agonists, highly selectively and concentratedly distributed in the hippocampus, septum, interpeduncular nucleus, amygdala and other brain limbic systems in the emotional center and serotonin 1A (5-HT) in the suture gland nucleus 1A ) receptor binding. Tandospirone and 5-HT 1A The affinity of the receptor is strong, and the affinity to other receptors is weak. 1A Receptor selectively binds to inhibit hyperactive serotonergic neural activity, making 5-HT 1A Receptor produces significant downregulation, prompting serotonin and 5-HT in post...

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Problems solved by technology

[0006] At present, the research reports on the preparation method of exomethylenetetrahydrophthalic anhydride include: Document 1 (Elements of Organometallic Chemistry, 1974: 92-94) discloses a method for understanding polydicyclopentadiene, which uses heating dicyclopentadiene To 180 ° C, high temperature distillation to obtain monocyclopentadiene, but the yield is less than 50%

WO2010101882 and Document 2 (Chem.pharm.bull. 1991, 39(9): 2288-2300) disclose the transformation method of repeated high-temperature dissolution and reflux to transform the inner methylene tetrahydrophthalic anhydride to obtain the outer methylene tetrahydrophthalic anhydride. Phthalic anhydride, but this method has defects such as large energy consumption, low yield, and long reaction time, and the total yield of the transformation product is only about 20%. Methylenetetrahydrophthalic anhydride as an inducer to induce the forward transition reaction

CN101880274A discloses a method for preparing exomethylenetetrahydrophthalic anhydride by using sodium light illumination transformation instead of high temperature transformation, but because this method cannot guarantee sufficient irradiation area, irradiation energy and irradiation uniformity of sodium light source in large-scale industrial production And other problems, so that it has great limitations in industrial applications

[0012] In the industrial depolymerization of dicyclopentadiene, the average yield of cyclopentadiene is less than 50%, resulting in a very low utilization rate of dicyclopentadiene and a large amount of waste that pollutes the environment

The existing depolymerization methods of dicyclopentadiene include liquid phase depolymerization method and gas phase depolymerization method, both of which require huge equipment and material input, and consume large amounts of energy, and produce a large amount of polysaccharides during the depolymerization process. Polymer or coke, which not only pollutes the environment, but also poses a great safety hazard

Among them, the liquid phase depolymerization method is more commonly used, but it is very easy to polymerize during the depolymerization process, resulting in a large amount of waste that is difficult to dispose of, which poses a great threat to production equipment and the environment, and has a low yield. Defects such as high cost

Compared with the liquid phase depolymerization method, the gas phase depolymerization method has a higher conversion rate, but in the depolymerization process, the coking of the material is very easy to occur and the reactor is blocked, which leads to great safety hazards and environmental threats. limited in industrial applications

[0013] (2) The transformation reaction of endomethylenetetrahydrophthalic anhydride needs to be carried out at high temperature (higher than 190°C), and the total transformation yield is low (only about 20%), or it needs multiple transformations and repeated refining. The amount of organic solvent used is large, the loss is large, the energy consumption is high, the production cycle is long, and the cost is high

[0014] (3) The total yield of exomethylenetetrahydrophthalic anhydride is low (only about 7%), and there are many reaction steps and each step requires the use of organic solvents, resulting in a large amount of organic solvents, large losses, high energy consumption, and production Defects such as long cycle time, high production cost, and serious environmental pollution

[0015] (4) The refining yield of the crude exomethylenetetrahydrophthalic anhydride is low (only about 31.4%), and a large amount of highly toxic organic solvents (such as toluene) are required for multiple refining, resulting in a large amount of organic solvent and a large loss , high energy consumption, long production cycle, high production cost, serious environmental pollution, and harmful to the health of operators

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